Selective ketalization of polyketo-5alpha-androstanes and 3-dimethyl ketals produced thereby



United States Patent 3,190,896 SELECTIVE KETALIZATION 0F POLYKETO-Su-ANDROSTANES AND S-DIMETHYL KETALS PRODUCED THEREBY Walter R. Benn,Deerfield, Ill., assignor to G. D. Searle & Co., Chicago, 111., acorporation of Delaware No Drawing. Filed Mar. 1, 1963, Ser. No. 262,2194 Claims. (Cl. 260-397.4)

The present invention relates to a novel process for the manufacture of3-dimethyl ketals of steroids possessing the 5a-androstane structure andespecially to a process for the selective ketalization of the 3-ketogroup of a 5a-androstane possessing additional potentially ketalizableketo groups.

This invention encompasses also the novel 3-dimethyl ketal of5u-androstane-3,6,17-trione.

The instant process is conducted by contacting the 3-keto-5u-androstanestarting material with methyl alcohol at or near room temperature in thepresence of an acid catalyst. Under these conditions, the S-keto groupreacts rapidly while other keto groups remain unaffected, thus producingthe 3-dimethyl ketal in substantially quantitative yield. In addition tothe high yields obtained, the present process possesses the advantage ofutilizing inexpensive reagents, i.e., methyl alcohol and an acidcatalyst. Suitable acid catalysts are typified by p-toluenesulfonicacid, perchloric acid, hydrochloric acid, and sulfuric acid. In thisconnection, an anhydrous catalyst is preferred in order to affordmaximum yields. As is mentioned above, the present process can becarried out effectively at room temperature, although the reaction maybe accelerated, in some cases, by warming in order to achievehomogeneity. Elevated temperatures may also be used but offer noadvantage. The rate of reaction can be increased also by avoiding anundue excess of methanol in order to allow the ketal to precipitate fromthe reaction mixture as it is produced, thus driving the equilibrium inthe desired direction. The process comprising the present invention isspecifically illustrated by the reaction of 5u-androstane-3,17-dionewith methyl alcohol and p-toluenesulfonic acid at 25-40 to afford5a-androstane-3,17-dione 3-dimethyl ketal. An additional example furtherdemonstrating the specificity of this process is the production of5a-androstane-3,6,17-trione B-dimethyl ketal by the reaction of5ot-androstane-3,6,17- trione with methyl alcohol in the presence ofp-toluenesulfonic acid.

The 3-dimethyl ketals of the present invention are useful asintermediates in the manufacture of compounds possessing usefulpharmacological properties. The aforementioned 5a-androstane-3,17-dione3-dimethyl ketal, for example, is allowed to react with sodiumborohydride in methanol to yield 17e-hydroxy-5a-androstan-3-one3-dimethyl ketal. Cleavage of the ketal function by reaction withhydrochloric acid in aqueous methyl alcohol results in17fl-hydroxy-5a-androstan-3-one, a well-known androgenic agent. Thisprocess for the conversion of Swandrostane-3,17-dione to17fl-hydroxy-5a-androstan-3-one is conveniently carried out withoutisolating the intermediates, resulting in high yields, i.e., 95-97%, ofthe product.

The invention will appear more fully from the exam ples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples, temperaturesare given in degrees centigrade C.).

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Quantities of materials are expressed in parts by weight except whereotherwise noted.

Example 1 displays a characteristic infrared absorption maximum at about5 .75 microns.

It is represented by the structural formula I,

Example 2 A mixture of one part of 5ot-androstane-3,6,l7-trione, 8 partsof methyl alcohol, and 0.01 part of p-toluenesulfonic acid monohydrateis allowed to stand at room temperature for about 15 minutes, resultingin precipitation of the solid product. This precipitate is collected byfiltration and dried to aflord 5 a-androstane-3,6,17-trione 3-dimethylketal, melting at about 211-214 and displaying characteristic infraredabsorption maxima at about 5.75 and 5.84 microns. An additional quantityof this ketal is obtained by adding to the filtrate one part ofpyridine, concentrating the solution to a small volume at reducedpressure, and collecting the resulting crystals by filtration. Thiscompound is represented by the structural formula 01130 CH O I 0 Example3 A methanolic slurry of 5a-androstane-3,l7-dione 3-dimethyl ketal,prepared according to the procedure of Example 1, is cooled by means ofan ice bath, and a solution of 8 parts of sodium borohydride in parts ofcold methanol is added. The cooling bath is removed, resulting in aninitial temperature rise to about 35, followed by a drop to roomtemperature. The total reaction time amounts to about one hour.

To the latter mixture containing 17 fl-hydroxy-5u-androstan-3-one3-dimethyl ketal is added successively 2 parts of acetic acid and asolution of 21.4 parts of concentrated hydrochloric acid in parts ofwater. Warming to about 45 results in dissolution of the suspendedsolids, at which time 70 parts of hot water is added, and the aqueousmixture is allowed to cool to room temperature. The precipitated productis collected by filtration and washed on the filter with methanol toyield pure 1718- hydrdxy-5a-androstan-3-one, melting at about l78-l81.Further pure material melting at about 177-180 is obtained by dilutionof the filtrate with water.

Example 4 The methanolic solution containing l78-hydroxy-5aandrostan-3-one 3-dimethyl ketal, prepared according toExample 3, is concentrated to a small volume under reduced pressure,then is extracted with ether. The resulting organic solution is washedwith water, dried over an hydrous sodium sulfate, and concentrated todryness at reduced pressure. Crystallization of the residue frommethanol containing a small amount of pyridine aflords pure17fi-hydroXy-5a androstan-3-one 3dimethyl ketal, melting at about201-203 with decomposition.

What is claimed is:

1. A process for the selective ketalization of the 3-keto group of aSoc-androstan-Zi-one possessing an additional keto function in at leastone of the 6- andl7-p'ositions and lacking substitution by large groupsat the 2 and/ or 4 positions, which comprises contacting thatSa-androstan- 3-one with methanol in the presence of an acid catalyst,thus affording the B-dimethyl ketal.

2. A process for the'rnanufacture of a 3-dimethy1 ketal of thestructural formula wherein X is a member of the class consisting ofmethylene and carbonyl radicals, which comprises contacting a compoundof the structural formula O Ha I 5 wherein X is a member of the classconsisting of methylene and carbonyl radicals, with methyl alcohol inthe presence of an acid catalyst.

3. A process for the manufacture of Sa-ahdrosfane- 3,l7-dione 3-dimethylket'al which comprises contacting 5a-androstane-3,l7-dione with methanolin the presence of p-toluenesulfonic acid.

References Cited by theExa'rniner UNITED STATES PATENTS 3/60 Oliveto etal. 260230.55

OTHER REFERENCES Amendolla et al., J.'Che'm. Soc., pp. 1226-33 (1954).Janot et al., Soc. Chim; de France, pp. 2109-13 (1961).

35 LEWIS cor'rs, Primary Examiner.

1. A PROCESS FOR THE SELECTIVE KETALIZATION OF THE 3-KETO GROUP OF AKA-ANDROSTAN-3-ONE POSSESSIG AN ADDITIONAL KETO FUNCTION IN AT LEAST ONEOF THE 6- AND 17-POSITIONS AND LACKING SUBSTITUTION BY LARGE GROUPS ATTHE 2 AND/OR 4 POSITIONS, WHICH COMPRISES CONTACTING THAT5A-ANDROSTAN3-ONE WITH METHANOL IN THE PRESENCE OF AN ACID CATALYST,THUS AFFORDING THE 3-DIMETHYL KETAL.